Medulloblastoma

NORD gratefully acknowledges Corey Raffel, MD, PhD, Professor of Clinical Neurosurgery
Department of Neurological Surgery, University of California, San Francisco, for assistance in the preparation of this report.

Synonyms of Medulloblastoma

primitive neuroectodermal tumor of the posterior fossa

General Discussion

Medulloblastoma is the most common malignant brain tumor in children. Medulloblastomas by definition occur in the cerebellum, which is the part of brain located at the base of the skull, just above the brainstem. The cerebellum is involved in many functions including coordination of voluntary movements (e.g., walking, fine motor skills) and regulating balance and posture. Medulloblastomas arise from primitive, undeveloped cells in the brain. Most medulloblastomas occur in infants and children. Less commonly, these tumors can develop in adults as well. Symptoms associated with a medulloblastoma include headaches in the morning that improve as the day goes on, recurrent vomiting and difficulty walking and with balance. Medulloblastomas can spread to other areas of the central nervous system. The exact cause of a medulloblastoma is unknown.

Signs & Symptoms

The specific symptoms associated with a medulloblastoma will vary from one person to another based upon the exact location and size of a medulloblastoma and whether the tumor has spread to other areas. Affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

The symptoms of medulloblastoma usually result from increased pressure within the skull (intracranial pressure). Medulloblastomas generally arise in or near the base of the skull, an area known as the posterior fossa. The posterior fossa contains the brainstem and the cerebellum.

Medulloblastomas typically involve the fluid-filled fourth cavity (ventricle) of the brain. The brain has four cavities called ventricles that are filled with cerebrospinal fluid (CSF) and joined by channels, through which CSF circulates. Because the tumor often fills the fourth ventricle, CSF circulation is obstructed, resulting in hydrocephalus. Hydrocephalus is a condition in which the accumulation of excess CSF in the brain causes a variety of symptoms, including repeated, often severe vomiting, lethargy and headaches that frequently occur in the morning and improve as the day goes on. Additional symptoms may include irritability, increased head size, and paralysis (paresis) of the muscles that help control eye movements (extraocular muscles).

Many infants and children with a medulloblastoma develop papilledema, a condition in which the optic nerve swells because of increased intracranial pressure. The optic nerve is the nerve that transmits impulses from the retina to the brain. Papilledema can cause reduced clarity of vision. Because many the symptoms associated with a medulloblastoma are nonspecific and often subtle, papilledema may the first sign that brings affected infants and children to the attention of a neurologist.

Children with medulloblastoma often have evidence of cerebellar dysfunction. Symptoms may include poor coordination, difficulty walking, and clumsiness (ataxia). Affected children may fall frequently and develop an unsteady, clumsy manner of walking (unsteady gait). They may tend to stand with their feet widely separated, stagger or sway when walking and easily lose their balance.

As a tumor grows or spreads, additional symptoms can develop. Such symptoms may include double vision (diplopia), rapid, jerky movements of the eyes (nystagmus), facial weakness, ringing in the ears (tinnitus), hearing loss and a stiff neck. Some children with double vision may tilt their heads in an effort align the two images.

Causes

The exact underlying cause of medulloblastoma is unknown. Most cases occur randomly for no apparent reason (sporadically).

Many cases of medulloblastoma are associated with chromosomal abnormalities. These abnormalities are not inherited (i.e., are not passed on from one generation to the next), but occur at some unknown point during a child’s development, even during the development of a fetus or embryo. Although medulloblastomas are associated with chromosomal changes, they are not inherited.

In individuals with cancer, malignancies may develop due to abnormal changes in the structure and orientation of certain cells. As mentioned above, the specific cause or causes of such changes are unknown. However, research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically).

Evidence suggests that, in approximately one-third to one-half of individuals with a medulloblastoma, tumor cells may have a specific chromosomal abnormality, known as isochromosome 17q, with associated loss or inactivation of certain genetic information. Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere).

An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in certain cases of medulloblastoma, there is duplication of the long arm and deletion of the short arm of chromosome 17. Some researchers suggest that such structural abnormalities of chromosome 17 may lead to inactivation of a gene on the chromosome that normally acts as a tumor suppressor, potentially leading to malignant transformation of certain cells. However, the implications of such findings remain unclear.

Additional chromosomal abnormalities have been identified in individuals with medulloblastoma including abnormalities on chromosome 1, 7, 8, 9, 10q, 11, and 16. How these various abnormalities play a role in the development of medulloblastoma is unknown. Further research is needed to determine the complex underlying mechanisms responsible for the development of a medulloblastoma.

In individuals with cancer, including medulloblastoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. Oncogenes that are associated with medulloblastoma include ERBB2, MYCC, and OTX2. Many medulloblastomas are characterized by alterations in specific molecular signaling pathways that result in uncontrolled cell growth. Pathways implicated in medulloblastoma include the Wnt pathway, the SHH pathway and the myc pathway.

In extremely rare cases, medulloblastomas occur in individuals who have certain inherited disorders including Gorlin syndrome (nevoid basal cell carcinoma), Turcot syndrome, Li Fraumeni syndrome, Rubinsten-Taybi syndrome, Nijmegen breakage syndrome, neurofibromatosis and ataxia-telangiectasia. Individuals with these disorders have an increased risk of developing a medulloblastoma. (For more information on these disorders, choose the specific disorder name in the Rare Disease Database.)

Researchers theorize that medulloblastoma originates from immature cells that are somehow prevented from maturing (i.e., differentiating) into more specialized cells, which have “intended”, specific functions within the tissue in question. Such immature or incompletely differentiated cells may grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body’s natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm).

Several different subtypes of medulloblastoma have been identified including anaplastic (large cell) medulloblastoma; classic medulloblastoma; desmoplastic nodular medulloblastoma; medulloblastoma with extensive nodularity (MBEN); medullomyoblastoma; and melanotic medulloblastoma. The various subtypes of medulloblastoma appear different on a cellular level, but as yet to not influence treatment options. However, in the future such distinctions may be used to develop novel, targeted therapies based on a particular subtype and other factors.

Extensive transcriptional profiling of human medulloblastomas has recently yielded a second and more precise classification system that stratifies medulloblastomas according to their mRNA expression profiles. Four subgroups with distinct mRNA signatures have been identified, and are presently categorized as WNT, Sonic hedgehog (SHH), Group 3 and Group 4.

Medulloblastomas in the WNT subgroup feature genetic alterations that affect members of the Wnt signaling pathway, which are linked to the processes of embryogenesis and oncogenesis. Mutations of the ß-catenin gene and monosomy 6 are among the more common genetic events that define this subgroup, and the incidence rate among males and females is approximately equal. WNT subgroup medulloblastomas tend to affect older children and are rare in adults. Among the different subgroups, WNT tumors have the best prognosis and clinical outcomes. The SHH subgroup is characterized by up-regulation of members of the SHH signaling family. Common genetic events exclusive to this subgroup are mutations in the genes for PTCH, the receptor of SHH, and SUFU, a negative regulator of SHH signaling pathway. SHH tumors are the most common subgroup of medulloblastoma found in infants and adults, and they carry an intermediate prognosis. Like the WNT subgroup, the incidence of SHH tumors is equal for males and females. Group 3 tumors are characterized by over-amplification of MYC and genes related to phototransduction and glutamate signaling. These tumors are also known for their high frequency of metastasis and have the worst prognosis of any medulloblastoma subtype. Group 3 tumors are extremely rare in adults, and are more prevalent in males than females. The last subgroup, currently known as Group 4, is characterized by up-regulation of genes related to neuronal or glutameminergic signaling. Although these tumors are common across all age groups, comparatively little is known about them. Like Group 3, Group 4 tumors are more prevalent in males and have a high tendency to metastasize. Their prognosis is considered intermediate.

Medulloblastoma is sometimes classified as a primitive neuroectodermal tumor or PNET. PNETs are a group of tumors that arise from primitive nerve cells in the brain. A medulloblastoma is sometimes referred to as a primitive neuroectodermal tumor of the posterior fossa.

Affected Populations

Medulloblastomas can affect individuals of any age, but occur most often in children under the age of 15 with a peak incidence between 3 and 9 years of age. Medulloblastomas are the most common malignant brain tumor in children. Approximately 80 percent of affected individuals are under the age of 15. Medulloblastomas are extremely rare in adults accounting for 1-2 percent of all cases of brain tumors in adults. In adults, most medulloblastomas occur in individuals between 20-44 years of age. Medulloblastomas are extremely rare in individuals over the age of 45.

In children, males are affected more often than females. However, in adults the ratio is the same. The exact incidence of medulloblastomas is not known and many different estimates are given the medical literature. Generally, medulloblastomas account for 2 percent of all primary brain tumors and 18 percent of all pediatric brain tumors. Approximately 1,000 new cases are diagnosed in children and adults each year in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of medulloblastomas. Comparisons may be useful for a differential diagnosis.

Different types of brain tumors may result in increased intracranial pressure and generalized symptoms similar to those potentially associated with medulloblastomas, such as vomiting, headaches, gait disturbances, changes in consciousness, visual impairment, enlargement of the head in young children, and/or other abnormalities. Such tumors may also result in additional generalized or more localized symptoms not typically associated with medulloblastomas; differ in average symptom duration before diagnosis; and/or have other clinical characteristics not generally seen with medulloblastomas. Clinical and neurological examination, complete patient history, advanced imaging techniques, and other diagnostic measures are typically required to confirm the presence of a brain tumor and to determine specific tumor type. (For further information, please see “Standard Therapies: Diagnosis” below or choose the specific tumor name in question as your search term in the Rare Disease Database.)

Diagnosis

Medulloblastoma is diagnosed based upon thorough clinical and neurological evaluation, detection of characteristic symptoms and physical findings, patient history, and specialized diagnostic tests. Such studies may include blood tests; evaluation of visual acuity, visual fields, and eye movements; the use of an instrument (ophthalmoscope) that visualizes the inside of the eyes (i.e., to detect papilledema); advanced imaging techniques; and/or other diagnostic tests.

The main specialized imaging technique used to diagnosis medulloblastoma is magnetic resonance imaging (MRI) of the brain and spine. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of organs and tissues. Experts indicate that, if available, MRI is preferable to computed tomography (CT) scanning as a diagnostic means for medulloblastomas since it may provide a better indication of tumor extent, possible invasion of the meninges, and spine involvement. An MRI is performed before and after a patient receives an intravenous injection of gadolinium-based contrast material. The contrast causes a tumor to appear as a bright mass (much brighter than surrounding tissue). When an MRI is unavailable, a CT scan may be performed. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of internal structures.

Gadolinium-based MRI of the spine may also be performed to detect whether a medulloblastoma has spread to the cerebrospinal fluid and the spine. In some cases, a lumbar puncture may also be recommended for analysis of tumor cells within the CSF. (During a lumbar puncture, a hollow needle is inserted into the spinal canal to withdraw CSF for analysis.) However, experts may advise that lumbar puncture is inadvisable (contraindicated) in most cases before tumor resection.

Surgical removal and microscopic examination (biopsy) of the affected tissue may be performed to confirm a diagnosis of medulloblastoma. Other diagnostic studies may also be conducted in some instances.

Standard Therapies

Treatment

The treatment of medulloblastoma may require the coordinated efforts of a team of medical professionals, including pediatricians; specialists in diseases of the nervous system (neurologists), the diagnosis and treatment of cancer (medical oncologists), and the use of radiation in the treatment of cancer (radiation oncologists); pediatric oncologists; oncology nurses; neurosurgeons; and/or other health care professionals. The specific treatment approaches used may depend upon tumor size, location, nature, stage, and/or progression; patient age and overall health; and other factors.

Aggressive surgery followed by radiotherapy and chemotherapy, which may be used alone or in combination, are the current standard used to treat individuals with medulloblastoma. Therapies that are effective in one group may not be effective in another group. For example, chemotherapy that has been effective in children and adolescents may be ineffective or less well tolerated in adults.

Surgery may be performed to obtain a biopsy sample, relieve pressure on the brain by draining CSF accumulation, and to remove as much as the tumor as possible without damaging surrounding brain tissue. Surgery is directed toward complete tumor removal or removal of as much of the tumor as possible. Some studies have indicated that the outcome improves when all of the tumor visible to a surgeon's eyes can be removed (gross total resection). However, gross total resection is not always possible. Shortly after surgery, advanced imaging techniques (e.g., CT, MRI) and other diagnostic methods may be conducted to determine how much of the tumor is left and to aid in the determination of appropriate, postoperative treatment approaches.

In rare cases, shunting may be recommended before surgery to remove the tumor. Shunting will help remove excess fluid and decrease intracranial pressure. Shunts are specialized devices that drain excess CSF away from the brain to another part of the body for absorption into the bloodstream. However, preoperative CSF shunting is not routinely conducted due to certain risks (e.g., herniation, possible facilitation of the spread of cancerous cells) and since hydrocephalus is alleviated by tumor removal in many individuals. Some patients may need a shunt after the operation for tumor removal.

Standard postoperative treatment often includes radiation therapy (radiotherapy) of the brain and spine (craniospinal irradiation) beginning approximately two to four weeks after surgery. During radiotherapy, radiation (via x-rays or other sources of radioactivity) is passed through selected regions of the body to destroy cancer cells and shrink tumors. Radiotherapy is provided in carefully determined dosages to help minimize damage to normal body cells. Radiotherapy is an important adjunct therapy because it can destroy microscopic cancer cells that are too small to be seen and may remain after surgery. These microscopic cells may lead to a recurrence of the tumor.

In advanced cases, recommended therapy may also include treatment with certain anticancer drugs (chemotherapy) during or after radiotherapy. Physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. Chemotherapeutic drugs that have been used to treat medulloblastoma include vincristine, lomustine, cisplatin, cyclophosphamide, carboplatin, or etoposide.

Chemotherapy may be given to infants and young children under the age of three instead of radiotherapy to avoid the potential long-term side effects of radiotherapy. In some cases, radiotherapy may be recommended when those children grow older.

Because there are fewer adults with medulloblastoma than children, effective treatment regimens have yet to be established for adults. The various chemotherapeutic drugs that have been used to treat children have been less effective in adults who often experience worse side effects.

Investigational Therapies

Many researchers are evaluating the safety and effectiveness (efficacy) of high-dose therapy with certain chemotherapeutic drugs–possibly in combination with radiation therapy and/or other treatments–followed by stem cell/bone marrow transplantation to help restore healthy bone marrow.

Researchers are also studying experimental drugs that target the specific underlying genetic makeup of tumor cells. These target therapies ideally would limit damage to surrounding tissue. More research is necessary to determine the long-term safety and effectiveness of such therapies for the treatment of individuals with medulloblastoma. Therapies designed to stimulate the body’s own immune system to combat the tumor are under investigation. In addition, the use of modified viruses that will kill only tumor cells but not normal cells is being investigated in the laboratory.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, in the main, contact:

Years Published

The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.

The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.

NORD's Rare Disease Database provides brief introductions for patients and their families to more than 1,200 rare diseases. This is not a comprehensive database since there are nearly 7,000 diseases considered rare in the U.S. We add new topics as we are able to do so, with the help of rare disease medical experts.

If you are seeking information about a rare disease that is not in this database, we would suggest contacting the Genetic and Rare Diseases Information Center (GARD) at the National Institutes of Health. NIH has the most complete database of rare diseases in the U.S.

Representatives of patient organizations whose medical advisors are interested in assisting NORD in creating a report on a disease not currently covered in this database may write to orphan@rarediseases.org.